R375S

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Arginine → Serine at position 375 · Transmembrane helix 3 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type R375 — ionic bond to E394

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DynaMut2 mutant · R375S

Mutant S375 — ionic bond to E394 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost3 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	E394	—	Lost
Hydrogen bond	W371	W371	Preserved
Hydrogen bond	E372	E372	Preserved
Hydrogen bond	T378	T378	Preserved
Hydrogen bond	D379	D379	Preserved
Hydrogen bond	E394	—	Lost
Polar contact	W371	W371	Preserved
Polar contact	E372	E372	Preserved
Polar contact	N373	N373	Preserved
Polar contact	L377	L377	Preserved
Polar contact	T378	T378	Preserved
Polar contact	D379	D379	Preserved
Polar contact	E394	—	Lost
Van der Waals	—	W371	Gained
Van der Waals	—	N373	Gained
Van der Waals	—	L377	Gained
Van der Waals	D379	—	Lost

Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.

Computational Predictions

DynaMut2 ΔΔG

-1.19kcal/mol

Destabilising — moderate

AlphaMissense

0.625

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.00080%

cDNA changec.1123C>A

ClinVar accessionVCV004744072

Last evaluated2026/01/12 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — R375S Variant Card

Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill

Arginine → Serine at position 375. Transmembrane helix 3. ClinVar Uncertain significance, AlphaMissense 0.625, DynaMut2 ΔΔG -1.19 kcal/mol (destabilising).

Identity

Field	Value
Variant	R375S (p.Arginine375Serine)
DNA change	c.1123C>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV004744072
Amino acid change	Arginine (R) → Serine (S)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 375	83.00 — well-folded
Domain	Transmembrane helix 3
Position context	Inside Transmembrane helix 3 · position 375 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 375 sits in a transmembrane helix (Transmembrane helix 3). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is positively charged (arginine — guanidinium, strong H-bond donor); the mutant is small polar (serine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.6248
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.19 (Destabilising)
Job ID	178092130195
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092130195

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2026/01/12 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	R375S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

(no conditions catalogued)

Research Path Decision Tree

ΔΔG < 2  + binding site affected   →  CATEGORY 3 — docking experiments
ΔΔG 2–4                            →  CATEGORY 2 — pharmacological chaperones
ΔΔG > 4                            →  CATEGORY 1 — gene therapy
pLDDT < 50                         →  CATEGORY 5 — IDR, experimental only
Stable fold + functional site hit  →  CATEGORY 4 — site-specific docking

Final Schema Categorization

Category 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=1.19 < 2 kcal/mol (fold intact) + AlphaMissense 0.625 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.19 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.625. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
R375S_molstar_viewer.html — interactive 3D viewer (auto-highlights position 375 with ball-and-stick + neighbors within 5Å)
R375S_variant_card.md — this card (source of truth)
R375S_variant_card.html — styled printable card
R375S_dynamut2_summary.html — clean offline DynaMut2 result card
dynamut2_result.json — structured result data
dynamut2_result_page.html — local snapshot of the Biosig result page (asset URLs absolutized)
R375S_wildtype_interactions.pse / R375S_mutant_interactions.pse — PyMOL sessions

Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas Every assumption documented. Every score sourced.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R375S PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.

Download R375S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.